Abstract Colorectal cancer is one of the most common cancers in both men and women in the United States and accounts for approximately 140,000 new cases annually. Hepatic metastasis, the dominant feature of life- limiting disease, occurs in approximately 20?50% of patients with colorectal cancer. Although regional treatment options, including hyperthermic isolated hepatic perfusion (HIHP) and percutaneous IHP, offer the benefits of both aggressive local treatment and limited systemic toxicity, the management of unresectable colorectal liver metastases remains a major unsolved issue and more effective novel regimens are needed. During the grant period, we will develop a novel strategy for targeted HIHP therapy. We hypothesize that a combinatorial treatment of targeted hyperthermia, the biologic agent Fc-TRAIL (immunoglobulin Fc domain fused tumor necrosis factor-related apoptosis-inducing ligand), and the chemotherapeutic agent oxaliplatin will be effective in treating unresectable colorectal liver metastases. The specific aims of this project are to (1) elucidate the mechanism of synergistic anti-tumor efficacy caused by Fc-TRAIL-based targeted multimodal treatment, and (2) investigate the preclinical efficacy of this combinatorial treatment in an IHP rat model. The proposed studies for the first aim will employ biochemical and molecular techniques to investigate multimodal treatment. For the second aim, we will employ a syngeneic hepatic metastasis rat model of colorectal carcinoma to study the efficacy of the multimodal treatment. We believe that our proposed regimen will provide information on the potential therapeutic advantage of an Fc-TRAIL-based multimodal treatment on patients.